1281P - Effect of Fra-2 expression on tumour immunogenicity and prognosis in KRAS-mutant lung adenocarcinoma

Background

Targeted therapies are available for lung adenocarcinoma (LUAD); however, more than 50% of patients either cannot benefit from them or become resistant, highlighting the need for alternative strategies. Our project focuses on FRA-2 (encoded by FOSL2 gene), a member of the AP-1 family that can act downstream of KRAS and EGFR pathways, two of the predominant genetic alterations observed in LUAD. Computational analyses of public databases have revealed a correlation between high FOSL2 expression and poor survival in KRAS-mutant LUAD. Consistently, tumour cell expression of Fra-2 has been found to correlate with shorter survival and higher tumour burden in a genetically engineered mouse model of LUAD driven by KRasG12V mutation and Tp53 loss.

Methods

Cell viability was assessed in primary tumour cells with Fra-2 gain- and loss-of-function, cultured from KRasG12V/Tp53-knockout mouse tumours. We prospectively collected fresh samples of resected LUAD tumours from patients with complete clinical and molecular annotations (N=27; 9 KRASmut), which were subjected to characterization by flow cytometry and IHC.

Results

In vitro analyses of primary tumour cells confirmed that overexpression of Fra-2 increases tumour cell viability. However, the absence of Fra-2 did not affect cell growth, suggesting that in vivo observations in Fra-2-deficient tumours could depend on anti-tumoral mechanisms that are extrinsic to tumour cells. In LUAD patients, the percentage of tumour cells expressing FRA-2 correlates with FRA-2 expression in immune cells as well as in cancer-associated fibroblasts (αSMA). FRA-2 also tends to show a positive correlation with proliferation (KI-67) and a negative correlation with T cells. A more detailed analysis by flow cytometry revealed that FRA-2 expression was related to an increased tumour density of regulatory T cells and decreased PD-1 expression, particularly in KRAS mutant tumours.

Conclusions

Our results suggest that FRA-2 could play a significant role as a mediator in the tumorigenic effects driven by KRAS mutations in LUAD, by promoting both tumour cell proliferation and immune evasion. These findings provide a new therapeutic opportunity in a clinically relevant setting.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Carlos III Health Institute.

Disclosure

L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme Corp, BMS, Janssen-Cilag International NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President. ASEICA (Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation president: Oncosur; Financial Interests, Other, member: Small Lung Cancer Group. All other authors have declared no conflicts of interest.